Herpes simplex virus (HSV) infects the eyes, replicates and travels through axons to the sensory neurons, where it becomes latent. Sporadically the virus can reactivate, return to the eye and cause corneal scarring and loss of vision. We have cloned a new HSV-1 gene, designated UOL, that is located in a genomic region previously suggested to be involved in viral virulence. Based upon two-hybrid system preliminary studies, UOL protein interacts strongly with ICAM-5 (intercellular adhesion molecules 5) from mouse brain. ICAM-5 is an important molecule in neuron-leukocyte interactions that is proposed to attract immune cells to the CMS. In pull-down experiments using lysates from mouse brains, UOL is able to pull-down ICAM-5. In addition, delayed immune response in immune lymphocytes infiltrating to CNS in wild type compared to that of UOL deletion virus infected mice. Thus, we hypothesize that UOL-ICAM-5 interactions play an important role in HSV virulence. To test this hypothesis, we propose the following specific aims: (1) Confirm that UOL-protein binds ICAM-5 in vitro and in vivo by protein-protein pull-down assays, co-immunoprecipitation, and confocal microscopy. (2)Confirm that UOL-ICAM-5 interactions are involved in HSV-1 neurovirulence. Several viral mutants will be constructed including anti-sense ICAM-5 oligonucleotides that can block ICAM-5 expression, UOL-shut off, and UOL-turn on mutants. By blocking ICAM-5 will significantly increase virulence of the HSV UOL mutant, while over express UOL should produce increased virulence. (3) Dissect the effects of immune cells by the interaction of UOL with ICAM-5 in CNS. ICAM-5 regulates immune response in CNS on the setting of infection. Immune lymphocytes infiltrating into CNS will be characterized and cytokines profile will be documented. Taken together, theses aims will shed new light on how HSV evades CNS immune system and may lead to the development of new treatments for HSV encephalitis.